PharmacologyTier 1Medical Sciences concept

Protein binding and free drug concentration (valproate, phenytoin)

Core concept

Only free (unbound) drug is pharmacologically active and available for clearance -- total (bound + free) concentration can mislead when binding changes
Hypoalbuminaemia (nephrotic syndrome, liver disease, malnutrition, critical illness) -> dec bound fraction -> inc free fraction at the same total concentration
Highly protein-bound drugs (phenytoin ~90%, valproate ~90%) are most affected by binding changes

In hypoalbuminaemia, measured total phenytoin/valproate can look "normal" or low while free (active) concentration is actually high -> toxicity at a "therapeutic" total level
Corrected phenytoin level (Sheiner-Tozer equation) adjusts total level for albumin -- or measure free phenytoin level directly when available
Valproate exhibits saturable (concentration-dependent) protein binding: as total concentration rises, binding sites saturate -> free fraction rises disproportionately -> free levels increase faster than total

Trap: a "low-normal" total phenytoin level in a hypoalbuminaemic patient with clinical toxicity (nystagmus, ataxia) is not reassuring -- check free level or correct for albumin
Displacement interactions (e.g. valproate displacing phenytoin from binding sites) transiently raise free phenytoin without changing total -- toxicity with a "normal" total level
Renal failure also alters binding (uraemic toxins compete for albumin sites) independent of albumin concentration itself

Same principle applies to other highly-bound drugs: warfarin displacement interactions, though clinical effect there is buffered by increased clearance of the freed drug
Total vs free distinction parallels ionised vs total calcium in hypoalbuminaemia -- same "correct for albumin" logic
Saturation kinetics here is a binding phenomenon, distinct from elimination saturation kinetics (zero-order, e.g. phenytoin metabolism) -- both apply to phenytoin but are separate mechanisms

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